With the increased use of proteins, such as antibodies, in clinical diagnostics and therapy, the need has arisen for more efficient, rapid, sterile production and purification methods.
Conventional approaches and tools for manufacturing cells or cell based products typically involve numerous manual manipulations that are subject to variations even when conducted by skilled technicians. Small quantities of cell-secreted product are produced in different ways. T-flasks, roller bottles, stirred bottles or cell bags are manual methods using incubators or warm-rooms to provide environments for cell growth and production. These methods are very labor intensive, subject to mistakes and difficult for large-scale production.
Production of cell secreted products can be achieved using a bioreactor (fibers, microfibers, hollow fiber, ceramic matrix, fluidizer bed, fixed bed, etc.) or using a stirred tank. This increases product concentration. The systems currently available are general purpose in nature and require considerable time from trained operators to setup, load, flush, inoculate, run, harvest, and unload.
Prior art techniques use a large-scale set-up wherein cells are being grown in batch bioreactors of e.g. 10000 liters (L). After a cultivation period, the antigens or antibodies of the batch are harvested within about 8 hours. Hereby, the 10000 L of suspension is clarified, the medium is exchanged (cell-culture medium replaced by buffer medium) by diafiltration, and the compounds are separated or purified by chromatography. A further filtration step may follow. The disadvantages of the prior art technique include the use of a big filter, a large amount of buffer medium, a large chromatography column and a considerable necessary amount of purified water. These amounts represent a considerable cost in terms of purified water production and water storage. A major disadvantage is the yield loss in the clarification step which is an essential step of this set-up for obtaining a diafiltration which is efficient enough to exchange the cell-culture medium within the limit of 8 hours.
Another drawback of the current available systems is the large investments that are required in terms of necessary installations, necessary space, etc. (the ‘hardware’) but also in terms of necessary material to produce the desired biomolecules. In addition, the necessary input of energy weighs tremendously on the required budget. Consequently, the huge investments to be made put a restrain on further development in the field of therapeutic antibody production, not only in the US and Europe, but also in the developing countries.
WO 2012/171030 describes an automated integrated system comprising a cell growth unit and purification unit. The system is still quite demanding in use and requires further optimization measures to improve ease of use and to increase output especially that said system is not scalable.
Accordingly, there is a need for systems and methods whereby cells and/or cell products can be cultured and if desired purified in a fully automated, rapid and sterile manner. Furthermore, there is a need in a methodology and system that provides a high product output with minimal investment cost and lowered capital expenditures (CAPEX) and operating expenditures (OPEX).
It is the aim of the current invention to provide methods and systems for the production of cells and/or cell products which overcome at least part of the above mentioned drawbacks and disadvantages. One object of the invention is to provide automated and integrated methods and systems for the growth and maintenance of cells but also for variable multiple downstream applications such as harvest and/or purification of cells and/or cell products (for instance, proteins or peptides).